Dinuclear alkyldiamine platinum antitumor compounds: a structure-activity relationship study

Six related dinuclear trans-platinum complexes, with the formula [[trans-PtCl(2)(NH(3))(L)](2)(mu-H(2)N(CH(2))(n)NH(2))](2+) (L = pyridine, 2-picoline, 4-picoline; n = 4, 6) and chloride or nitrate anions, are compared with known cytotoxic dinuclear compounds (L = NH(3); n = 4, 6) that overcome cisplatin resistance. The cytotoxicity of the compounds was determined in L1210 murine leukemia and L1210/2, a cisplatin-resistant derivative. Unlike the L = NH(3) compounds, the substituted n = 4 compounds are more susceptible toward the resistance mechanisms in L1201/2. The n = 6 compounds, however, have comparable IC(50) values in both cell lines. In general, the substituted compounds are less cytotoxic than their NH(3) counterparts. After incubation with equimolar concentrations, the amount of platinum bound to cellular DNA was determined. The compounds show comparable binding, except for the sterically hindered 2-picoline compounds that bind significantly less. The amounts of platinum bound to DNA do not correlate with the cytotoxicity data. As DNA is considered to be the cellular target of platinum antitumor drugs, structural details of the DNA adducts probably account for the differences in cytotoxic activity.